Re-evaluating the impact and cost-effectiveness of pneumococcal conjugate vaccine introduction in 112 low-income and middle-income countries in children younger than 5 years: a modelling study

Summary Background Streptococcus pneumoniae has been estimated to cause 9·18 million cases of pneumococcal pneumonia, meningitis, and invasive non-pneumonia non-meningitis disease and 318 000 deaths among children younger than 5 years in 2015. We estimated the potential impact and cost-effectiveness of pneumococcal conjugate vaccine (PCV) introduction. Methods We updated our existing pseudodynamic model to estimate the impact of 13-valent PCV (PCV13) in 112 low-income and middle-income countries by adapting our previously published pseudodynamic model with new country-specific evidence on vaccine coverage, burden, and post-introduction vaccine impact from WHO–UNICEF estimates of national immunisation coverage and a global burden study. Deaths, disability-adjusted life-years (DALYs), and cases averted were estimated for children younger than 5 years born between 2000 and 2030. We used specific PCV coverage in each country and a hypothetical scenario in which coverage increased to diphtheria–tetanus–pertussis (DTP) levels. We conducted probabilistic uncertainty analyses. Findings Using specific vaccine coverage in countries, we estimated that PCV13 could prevent 697 000 (95% credibility interval 359 000–1 040 000) deaths, 46·0 (24·0–68·9) million DALYs, and 131 (89·0–172) million cases in 112 countries between 2000 and 2030. PCV was estimated to prevent 5·3% of pneumococcal deaths in children younger than 5 years during 2000–30. The incremental cost of vaccination would be I$851 (510–1530) per DALY averted. If PCV coverage were increased to DTP coverage in 2020, PCV13 could prevent an additional 146 000 (75 500–219 000) deaths. Interpretation The inclusion of real-world evidence from lower-income settings revealed that delays in PCV roll-out globally and low PCV coverage have cost many lives. Countries with delays in vaccine introduction or low vaccine coverage have experienced many PCV-preventable deaths. These findings underscore the importance of rapidly scaling up PCV to achieve high coverage and maximise vaccine impact. Funding Bill & Melinda Gates Foundation and Gavi, the Vaccine Alliance.


STUDY DESIGN AND MODEL STRUCTURE 1.Study design
This model is a re-evaluation of the epidemiological impact of pneumococcal conjugate vaccine (PCV) on children under-5 by adapting the combination of two existing models from Chen et al. 1 and García et al. (which presents the linkage of the ecological model from Chen et al. 1 and the UNIVAC model from García et al. 2,3 ) using a decision tree model (Figure 1a).

Vaccine coverage
In total, we tracked 30 birth cohorts of children under-5 between 2000 and 2030 in 112 lowand middle-income countries, including 73 Gavi countries.Accounting for vaccine introduction, estimates in the no vaccination scenario were multiplied by the predicted IRRs from the pseudo-dynamic model adjusted for the abovementioned characteristics to reflect the burden of diseases after PCV introduction.The impact of PCV introduction was estimated by multiplying the predicted incidence risk ratio (IRR) from our 2019 model, 1 to disease estimates from the literature. 4The IRR was adjusted with WHO-UNICEF vaccine coverage.We used country-specific annual vaccination coverage data from WHO-UNICEF 5 up to 2019.We then compared the estimates from the no vaccination and vaccination scenario.
We present the under-5 vaccine coverage based on two scenarios (Figure 1b).The overall line is weighted by population sizes of countries.For the first scenario, national-level PCV coverage from 2000 to 2019 was obtained from WHO-UNICEF Estimates of National Immunization Coverage (WUENIC) 5 and assumed to stay the same for the subsequent years (2020 to 2030).By 2014, at least half the countries had introduced PCV.For the second scenario, from 2000 to 2019, similar to the first scenario, national-level PCV coverage estimates up to 2019 were obtained from WUENIC. 5 However, from 2020 to 2030, we assumed that countries' PCV coverage in 2020 to 2030 would increase to their respective countries' 2019 diphtheria-tetanus-pertussis (DTP) coverage levels, obtained from WUENIC. 6

Figure 1a
Disease pathways for a birth cohort in the vaccination and no vaccination scenario PCV: pneumococcal conjugate vaccine Clone 1 Disease pathway: repeats the same pathway as the PCV introduction but with different transition probabilities.The thick solid lines are the mean under-5 coverage of the countries.The dotted lines are the country-specific under-5 coverage.We assumed that the under-1 coverage is constant from 2019; thus, the under-5 will be constant from 2024 (see the next paragraph).DTP: diphtheria-tetanus-pertussis; PCV: pneumococcal conjugate vaccine.
Using Bosnia and Herzegovina as an example, we illustrate why under-5 coverage will only be constant from 2024.Bosnia and Herzegovina was one of the 31 countries without PCV in 2019.

Updated ecological vaccine impact
A recent systematic review conducted amongst under-5 in low-and middle-income countries found that although the introduction of PCV has led to a decrease in the prevalence of vaccine-type (VT) carriage, the prevalence of non-vaccine-type (NVT) carriage has increased due to serotype replacement. 7The authors found that the carriage of NVTs could increase up to 74.1% post-vaccination.
Countries with high under-5 coverage were assumed to receive the full impact, but we accounted for the time taken to eliminate VT IPD and the vaccine coverage required to reach full impact.The updated model is an extension of Chen et al. 1 model by incorporating three new model characteristics as explained in the main paper.First, the previous model assumed that the time taken to the near elimination of VT IPD was two years, but recent evidence suggests this may be closer to five years. 8Second, 100% PCV coverage was assumed as only some LMICs had post-introduction coverage data.Third, with this high PCV programme coverage, countries were assumed to reach equilibrium in VT carriage with existing PCV coverage and herd effects. 1 Lastly, as the evidence of the impact of PCV against nIPD is unclear, 9 the previous model assumed the same PCV impact for non-invasive pneumococcal disease (nIPD) and IPD pneumonia. 1However, it is likely that PCV effectiveness differs against disease with varying levels of invasiveness.Thus, this study updates our previous estimates by combining a country-specific model with emerging evidence on the real-world impact of PCV vaccine coverage.Below is a detailed description of the extension not explained in the main paper.

Time taken to the near elimination of VT IPD
A recent systematic review and meta-analysis had shown that the time taken to the nearelimination of vaccine-type IPD could be longer than the previously assumed two years. 8sing the definition of near-elimination of vaccine-type IPD as the time required to reduce corresponding disease by 90%, the authors found that for children under-5, the mean period to attain 90% reduction for all PCV7 serotypes was 4•6 years (95% CrI: 3•9-6•0).Hence, we updated the model with the year-on-year reductions in vaccine-type IPD, until near elimination of vaccine-type IPD was achieved.Using results from a systematic review and meta-analysis by Shiri et al. 8 specific for children under five and PCV7, we fitted a log-linear model to interpolate the percentage reduction in the incidence of IPD due to PCV7 serotypes for one to five years after vaccine introduction.As defined by the study, near elimination of IPD is the time required to reduce disease by 90%.Assuming 0% elimination of vaccine serotypes (VT) IPD upon vaccine introduction, and the findings from the meta-analysis that 1.2 years and 4.6 years are required to reduce VT IPD by 50% and 90% respectively, we estimated that the percentage elimination of VT IPD for 1 to 5 years post-vaccine introduction was 42%, 64%, 78%, 87% and 92% (Figure 2).We referenced evidence from PCV7 because the vaccine impact used was estimated by Flasche et al. 10 was modelled using PCV7.Due to the lack of evidence, we assumed that IPD and nIPD take the same time to reach the near elimination of VT disease.

Vaccine coverage required to reach full vaccine impact
To account for each country's vaccination coverage, we started with annual average PCV coverage in children under-5 using vaccine coverage for three doses, accounting for countryspecific vaccine introduction year. 2,11We estimated the average coverage achieved for each age category (under 1, 1 to 2, 2 to 3, 3 to 4 and 4 to 5 years) from UNIVAC's timeliness by the week of age. 12We fitted a linear regression model to estimate the vaccine coverage needed for IPD to be reduced by 90%, as defined by the authors, to achieve near vaccine-type IPD elimination. 8The pseudo-dynamic model assumed that vaccine-type carriage would be eliminated at high PCV coverage.We used published studies to determine that 82•1% (95%CI: 46.7-117) PCV coverage was needed to reduce vaccine-type IPD by 90%.Thus, we assumed that approximately 82% of vaccine coverage is required to reach full impact.This coverage value was estimated using evidence from four studies [13][14][15][16] in Kenya, Gambia, Israel, and the United Kingdom about the maximum VT IPD reduction following vaccine introduction.For each study, we identified the PCV coverage, and the reduction in pneumococcal disease.These results were then fitted into a linear regression and used to estimate the mean coverage required to achieve a 90% reduction (Figure 3).We did not account for different vaccine impacts from receiving one or two doses, or waning vaccine protection over time.In our study, meningitis and NPNM were classified as invasive pneumococcal diseases (IPD).For pneumococcal pneumonia, based on a study conducted in The Gambia 17 for children, we assumed that 14.8% of the disease burden was IPD.This was estimated by assuming that 13.35% 4 of clinical pneumonia in the placebo group (n = 2284, Table 3 17 ) was attributable to pneumococcus.The proportion of IPD pneumococcal pneumonia can thus be estimated by taking a ratio of the number of IPD radiological pneumonia (n = 45, Table 4 17 ) to the number of pneumococcal clinical pneumonia cases (n = 2284 x 0.1335).This assumption was different from the earlier model by Chen et al. 1 , where they assumed 24.8% of pneumonia to be bacteraemic based evidence amongst adults 18 due to the lack of evidence.
1.3.4Differentiated PCV impact on nIPD pneumonia from experts A panel of experts on pneumococcal epidemiology and microbiology was assembled to input on the parameters and assumptions to be used in the model.A meeting was held over Zoom on 3 August 2021 for members able to join; others were consulted by email.
The panellists continued to provide input during and after the meeting and also shared a slide on VE against AOM compared to IPD and pneumonia.The team continues to follow up on the suggestions from the panellist.The team continued to exchange follow-up discussions until 7th December 2021 via email, where panellists provided inputs and shared published literature relevant to our study.After this, the model parameters were confirmed.Finally, the vaccine impact assumptions were also confirmed with Anthony Scott via email.
Based on a study conducted in Gambia, 17 we assumed that 14•8% of pneumonia was bacteraemic, and the rest was nIPD pneumonia.This was estimated by assuming that 13•4% of clinical pneumonia in the placebo group was attributable to pneumococcus. 4The panel of pneumococcal experts was presented with questions about PCV effectiveness and disease endpoints and agreed on the assumption for PCV impact on nIPD to be 60% of the PCV impact on IPD.This 60% was estimated by assuming the midpoint for the vaccine efficacy (VE) against VT carriage and IPD as a proxy for the VE against nIPD.We assumed the lower bound of the VE against carriage for hospitalised children as the VE against carriage at 11.4% (results from Table 3: 39.1%; 95% CI: 11.4-58.1)from the study conducted by Chan et al. 19 in Mongolia.As the same study did not provide VE against IPD, we assumed VE against IPD from a Cochrane Review by Lucero et al. 20 at 58% (95% CI: 29-75).Taking the midpoint of the two VE gives 34.7% for the VE against nIPD.This is about 60% of the VE against IPD.Furthermore, we assumed that vaccine impact on pneumococcal AOM was the expected number of AOM outcomes in a vaccination scenario multiplied by the expected outcomes with the expected PCV coverage and vaccine efficacy for each vaccination dose.Vaccine efficacy for pneumococcal acute otitis media was assumed to be 20% based on a Cochrane Review. 21

MODEL PARAMETERS
The model evaluated the impact of PCV in a total of 112 low-and middle-income countries, including 73 Gavi countries.Among the 73 Gavi countries, Mongolia was the first to transit out of Gavi's support to fully finance their PCV immunisation programmes in 2015, 22 followed by Bhutan, Indonesia, Timor-Leste and Ukraine. 22These countries were categorised into five of the six UN regions available (Africa, Asia, Europe, Latin America and Oceania).Countries in each region are listed in Table 2 below together with their respective PCV introduction details.

PCV introduction details
Among the 81 out of 112 countries with PCV coverage by 2019, the two main PCVs currently used in infant immunisation programmes are PCV10 (n=17) and PCV13 (n=63), with one country using a mix of PCV10 and PCV13 (n=1).4][25] Most countries adopt a 3-dose schedule, where children receive either three primary doses at two, four, and six months of age, without a booster dose (the 3+0 schedule) or two primary doses at two and four months of age, followed by one booster dose at 12-15 months of age (the 2+1 schedule). 26,27These countries also have different vaccine coverage. 2,3,11,28Countries with low or no PCV coverage also tend to have high disease incidence among the under-5. 1,2,29Disease burden estimates (Table 3) were obtained from a global burden study by Wahl et al.. 4 The study provides country-specific incidence and mortality rates for pneumococcal pneumonia (severe and non-severe), pneumococcal meningitis and NPNM (severe and nonsevere).Based on the World Health Organisation, severe pneumonia is defined as having any general danger signs, chest indrawing (symptom or visual) or stridor in a child with a cough or difficulty breathing. 30This definition was used instead of the WHO updated definition in 2013 31 as they informed most impact studies from pre-vaccination surveillance.The risk of disabling sequelae from pneumococcal meningitis was obtained from a review study 32 to project the incidence of meningitis sequelae.Furthermore, incidence rates for pneumococcal AOM were obtained from a global systematic review, 33 assuming that 20% of the burden was attributed to Streptococcus pneumoniae. 346][37] For severe diseases, we assumed the duration of illness to be ten days 38,39 .Pneumococcal meningitis sequelae were assumed to last 50 years.In addition, only severe diseases and diseases related to meningitis led to mortality as published by Wahl et al.. 4 Consistent with UNIVAC, we assumed pneumococcal mortality rates would decrease over time (using the same rate of decrease reported for all-cause under-five deaths) in the absence of vaccination, due to improvements in access to care and living standards.For each birth cohort under five, disability-adjusted life years (DALYs) were estimated in this model by taking the sum of the number of years lived with disability and years of life lost.The number of years lived in disability was estimated by multiplying the number of cases by the DALYs weights, the percentage of healthy time lost, from GBD 2019 40 and the duration of illness (assumed as with the UNIVAC model).The years of life lost was estimated by multiplying the number of deaths by the life expectancies taken from the VIMC secretariat, obtained from the UN World Population Prospects. 414 Probabilistic analysis

Healthcare cost
The price per dose was assumed to be $15•68 for non-Gavi eligible countries and $3•05 (plus 20% tail price) for Gavi-eligible countries.A freight cost of 6% of the vaccine price, a 5% wastage rate, and a buffer stock of 25% of the first-year vaccine needs were included.Vaccine administration using five minutes of nurses' time to administer the vaccine and related injection supplies were included.Health-care costs included treatment in the hospital for all disease presentations except acute otitis media, for which outpatient costs were used.We also accounted for care-seeking behaviour for nIPD pneumonia and acute otitis media.We used the cost estimates as our earlier paper for comparability, 1 where costs for meningitis in low-income and middle-income countries were extracted. 42Costs for pneumonia were modelled from data in the WHO-CHOICE database, 43 and a 2016 systematic review. 44All unit prices were converted to 2015 international dollars ($), to facilitate comparisons with our previous findings. 1e costs of treating a patient with pneumococcal disease (meningitis, pneumonia, or NPNM invasive pneumococcal disease) were predicted using the best-fit model generated from data extracted from the literature.PCV cost-effectiveness analysis (CEA) studies were found through literature review and/or included in four main systematic reviews; from those two costing studies and 27 CEA studies were selected and used. 42, The osts were extracted and converted into International dollars at corresponding years the studies reported and then adjusted to 2015 using the ratio between GDP per capita PPP in year 2015 and those corresponding years.
We used international dollar I$, as it is widely used for international comparisons, and we present results mainly on a regional basis.The I$ was comparable to the amount of goods and services a U.S. dollar would buy in the United States for the cited country/Region, accounting for its purchasing power.Other relevant similar studies have also used I$, for example, Sinha's study on 72 developing countries: Sinha A, Levine O, Knoll MD, Muhib F, Lieu TA.Cost-effectiveness of pneumococcal conjugate vaccination in the prevention of child mortality: an international economic analysis.Lancet 2007; 369: 389-96.

Meningitis
Hospitalisation costs for Meningitis in low-middle income countries (LMIC) were extracted from a study by Portnoy et al that predicted costs for all LMICs by conducting a systematic review and extrapolating data to set up a database on cost of care for childhood meningitis. 42

Pneumonia
Hospitalisation costs for pneumonia were extracted from a study by Zhang et al., which conducted a systematic review of studies providing the cost of childhood pneumonia and also included unpublished data at that time. 44In their study the cost for LMICs was extracted from severe pneumonia data which mean is 242•7 USD 2013 (and also I$ 2013).As costs per episode for each country, were not available, we used WHO-CHOICE inpatient costs per day costs per day multiplied by 3•9 days as a proxy for costs per episode. 76The 3•9 days value was the average length of stay for pneumonia disease based on average length of stay for pneumonia in the United States. 77The resulting values were converted to International dollars of year 2015 (I$ 2015).To incorporate this information, we used weighted averages, with weights being the population size under five years of age, and the resulting weighted costs were compared with the extracted costs from Zhang et al. 44 We use the resulting value as a multiplicative factor.Finally, we applied this factor to the costs that we have generated.The multiplicative factor for LMIC was 1•18.

NPNM
53][54][55][56][58][59][60][61][62][63][64][65]67,[69][70][71][72][73][74][75] As the available costs were skewed, we used the logarithm of costs as our outcome.The predictors used were the logarithm of GDP per capita PPP in year 2015 and UN regions indicators.In search for the best fitting model, we used stepwise regression with AIC criterion.The resulting model was: The adjusted R-squared was 65•5%.To transform back to cost, we needed to have a correcting factor. 78The correcting factor equals to the sum of the expected residuals.In this case, it was 1•108.Therefore, the cost model used was: Through this model, we predicted the costs of all the countries, including the 29 countries whose data were used to generate the model.

AOM
[58][59][60][62][63][64][65][66][67][69][70][71][73][74][75] As the resulting costs were skewed, we used the logarithm of costs as our outcome.The predictors used were the logarithm of GDP per capita PPP in year 2015 and UN regions indicators.In search for the best fitting model, we use stepwise regression with AIC criterion.The resulting model was: The adjusted R-squared was 42•8%.To transform back to cost, we had a correcting factor. 78The correcting factor equals to the sum of the expected residuals.Here, it was 1•218.Therefore, the cost model was: Through this model, we predicted the costs of all the countries, including the 25 countries whose data were used to generate the model.

Incremental cost-effectiveness ratios (ICERs)
We estimated the incremental cost-effectiveness ratio (ICER) by comparing the introduction of PCV-13 to no PCV use or [(Cost in PCV-13 -Cost in no vaccination)/(DALYs averted)].The mean of 1000 ICERs bootstraps were calculated on International dollars I$ (2015) and DALYs.We compared with different willingness-to-pay thresholds.However, as the willingness-to-pay study was US-based, it might not be representative of low-and middle-income countries.As such, we considered using a previously common rule of thumb, where an intervention is cost-effective if a healthy year is gained at less than three times the GDP per capita. 79We also compared the resulting ICERs with the GDP per capita (PPP) as it has been traditionally used as an indicative threshold to indicate when an intervention is cost-effective. 80The ICERs were compared with the GDP per capita (PPP) of each region, calculated by summing over population-weighted figures for each country.Table 6 presents the undiscounted rates.The global ICER is estimated to be $821 per DALYs averted.If PCV coverage is increased to DPT coverage levels from 2020, it will require more investment in vaccination especially for countries without PCV, and the ICER will increase to $1310 per DALY averted.This is due to the increased cost of vaccination, particularly for countries without PCV to be protected for the next 10 years to 2030.However, in the full protection scenario, the ICER will drop to $657 per DALY averted due to the huge reduction in DALYs across 30 years of protection.All the resulting ICERs are presented with a 3% discount rate applied to costs and utility outcomes in the manuscript.The resulting predicted incidence rate ratio are as follows: =  + 1  + 1 c is the odds of vaccine-type carriage d is the odds of IPD λ is the proportion of vaccine-type carriage replaced by non-vaccine-type (our study assumed to be 1) Thus, under these assumptions, the predicted IRR can be treated as the maximum reduction in IPD achievable from a vaccination programme.The pseudo-dynamic model was validated using serotype-specific carriage in LMICs 81 and post-vaccine introduction data from high-income countries, which we extrapolated to LMICs due to a lack of post-introduction data from these settings.Since then, new LMIC data have emerged, allowing us to refine our assumptions.
For the vaccine coverage, we used real-world PCV coverage from 2000 to 2019 and 2019 PCV coverage for future years.Third, the UNIVAC model, a commonly used model, was used 2,3 .Fourth, using the updated pseudo-dynamic algorithm, we used under-1 DTP vaccine coverage 6 from 2000 to 2019 and 2019 DTP coverage for future years.Lastly, we considered the previous pseudodynamic algorithm from Chen et al. 1 with full protection.The percentage reductions are presented in Table 8.
The PCV impact on nIPD pneumonia was larger in the 2019 model as the 2019 model assumed the same vaccine impact for IPD and nIPD (Figure 4).The other two improvements to the updated model, namely (i) the near elimination of VT IPD and (ii) vaccine coverage required to reach full vaccine impact, while useful to incorporate real-world evidence, did not have an influential impact on IPD burden (Figure 4 (solid and dotted red line); Table 7).
Our updated model also accounted for the longer time needed to achieve maximum impact since PCV introduction.Furthermore, the year of PCV introduction based on actual data was assumed to start much later (Table 2) than 2000 in our previous model.We also assumed declining mortality rates over time due to improved living standards. 2When we updated our previous model to include the year of PCV introduction and PCV coverage, the relative impact of PCV was similar to current findings (Table 8 and Figure 4).Our analysis also estimates smaller relative reductions in pneumococcal burden compared to previous estimates from the Vaccine Impact Modelling Consortium (VIMC), 82 where the authors assume continued improvements in PCV coverage and new country introductions to 2030.Thus, the delays in vaccine introduction and lower PCV coverage rates in LMICs have cost the lives of many children under-5.
Our analysis also estimates smaller reductions in pneumococcal burden compared to previous estimates from the Vaccine Impact Modelling Consortium (VIMC), 82,83 which estimated that PCV would avert 2.8 million deaths and 190 million DALYs in 112 highest-burden countries in 2000-2030.These rely on two static models (UNIVAC and the Lives Saved Tool), neither of which incorporate indirect effects like herd immunity and serotype replacement.While herd immunity would be expected to increase vaccine impact, most of the effect is in older adults which are not captured in any of the analyses and only constitute a small portion of the pneumococcal burden in LMICs.In addition, a recent systematic review conducted amongst under-5 in low-and middle-income countries found that although PCV introduction decreased the prevalence of vaccine-type (VT) carriage, the prevalence of non-vaccine-type (NVT) carriage has been shown to increase due to serotype replacement, where carriage of NVTs could increase up to 74.1% post-vaccination 7 .As such, serotype replacement would diminish vaccine impact.Additionally, the VIMC models assumed continued improvements in PCV coverage and new country introductions to 2030, whereas we assumed that coverage would remain static after 2019.Research in LMICs also reports a limited number of cases involving vaccine serotypes continue to be transmitted.In South Africa, the incidence rate of PCV7 serotype IPD among children under-2 decreased from 32.1 to 3.4 cases per 100,000 person-years when PCV7 coverage reached 81%. 84This trend was mirrored in Kenya, where the PCV10-serotype IPD incidence rate dropped from 60.8 to 3.2 cases per 100,000 personyears with PCV10 coverage at 87%. 16 Other studies have also projected similar outcomes regarding the persistence of vaccine types.In Mongolia, despite achieving 100% vaccine coverage, there was a decrease in vaccine-type carriage from 29.1% to 13.1%. 19In Nigeria, a prevalence drop from 21% to 12% was observed with 84% vaccine coverage. 85ere are other limitations in addition to those mentioned in the main paper.Firstly, the carriage in under-5s could be influenced by post-vaccination changes in the immune status of people older than five years, which we did not directly account for.Indeed, a study in Kilifi, Kenya, estimated that the main contributor to the force of pneumococcal infection was school-aged children 86 .By ignoring these second-tier effects (under-5 vaccination reducing carriage in older children, which further reduces carriage in under-5s), our estimates might be more conservative.Next, since quantitative evidence on herd protection and serotype (and species) replacement for AOM are sparse, we modelled vaccine impact on AOM using a fixed vaccine efficacy of 20% instead of trying to model serotype dynamics.As such, unlike the other disease outcomes, we could only account for the direct impact of vaccination on AOM.As vaccine coverage can also vary significantly across different settings, by assuming uniform coverage, we may not have accounted for the disparities in vaccine access within countries.Notably, many countries that have yet to introduce PCV into their routine schedules are middle-income countries with no access to pooled procurement, possibly indicating that high vaccine prices may be a barrier to wider introduction.We encourage future research to explore these nuances in greater detail for countries where data is available to provide a more comprehensive understanding of the impact of pneumococcal vaccination within the country.In addition, previously, thresholds of 1 to 3 times GDP per capita were commonly used in global analyses, but they have now been widely criticized for failing to represent actual health opportunity costs in most countries. 79,87 10 and vaccine timeliness from the UNIVAC model from García et al 2,3 ).Assumptions: (i) Herd immunity and serotype replacement, (ii) complete VT IPD elimination, (iii) 82.1% vaccine coverage required to reach full vaccine impact and (iv) differentiated PCV impact on nIPD pneumonia.Details were explained in the methods section.
(3) UNIVAC model: UNIVAC (adjusted for vaccine coverage and vaccine efficacy), exclude indirect effects from García et al 2,3 ).Vaccine coverage and pneumococcal disease age distributions were estimated by week of age <5 years (rather than averaged for each full year of age).The model assumed 58% vaccine efficacy against all types of IPD using estimates from a meta-analysis of clinical trials.The model did not adjust for indirect effects (herd effects, type replacement) over time.(

Table 1 .
Bosnia and Herzegovina under -1 and under-5 vaccine coverage for the scenario with PCV introduction at DTP coverage in 31 countries without PCV in 2019 Bosnia and Herzegovina had yet to introduce PCV as of 2019.b We assume the PCV coverage from 2020 to 2030 is Bosnia and Herzegovina's 2019 DTP vaccine coverage.c The 2020 under-5 coverage is computed using the under-1 coverage from 2016 to 2020.

Figure 2
Figure 2 Years required to eliminate PCV7 serotypes

Figure 4 .
Figure 4. Comparison of outcomes for 112 countries by diseases IPD and nIPD pneumonia across different impact methods.

Table 2
PCV introduction details by regions and countries

Table 3
Pre-vaccination incidence and mortality rates per 100,000 population among children under five years of age

Table 4 .
Parameters for probabilistic sensitivity analysis

Table 5
below summarises the average healthcare cost across diseases and regions.

Table 5 .
Mean healthcare cost by disease and region

Table 6 .
Incremental cost-effectiveness ratios compared to no vaccination scenario ($ per DALYs averted, undiscounted) over 30 years, from the health-system perspective (undiscounted).

reduction using PCV coverage (compared to no vaccination), 2000-2030
Using respective year's PCV coverage data from 2000 to 2019, using 2019 PCV coverage data from 2020 to 2030.(3)DPT coverage scenario: Using respective year's PCV coverage data from 2000 to 2019, using 2019 DTP coverage data from 2020 to 2030.IPD: invasive pneumococcal diseases, which represents the sum of pneumococcal meningitis, pneumococcal non-pneumonia, non-meningitis, and invasive pneumococcal pneumonia nIPD: non-invasive pneumococcal diseases (2)PCV coverage scenario: